Pancreatic ductal adenocarcinoma is virtually invariably a fatal disease, and is characterized by invasive and metastatic progression, as well as a striking resistance to conventional therapeutic approaches. Early pancreatic non-invasive lesions, known as pancreatic intraepithelial neoplasia (PanIN) are believed to represent initiating lesions in the generation of PDAC. Importantly, PanINs exhibit very limited proliferation, both in human pancreas and in mouse models of cancer, despite the activation of the mitogenic Ras pathway. The precise molecular pathways that restrict the progression of early PanIN lesions to more aggressive lesions remain for the most part elusive. Identifying and targeting these pathways is likely to represent new therapeutic opportunities for the treatment of pancreatic cancer. Using genetically engineered mice and cells, we have recently demonstrated that the histone deacetylase (HDAC)-associated Sin3B protein is required for cell cycle withdrawal and senescence induced by expression of oncogenic Ras. Importantly, we have demonstrated that Sin3B protein levels strongly increase in early PanIN lesions compared to normal pancreas, but decrease as the tumor progresses. These observations strongly suggest that Ras-driven cell cycle withdrawal, mediated by Sin3B-dependent repression of pro-proliferative genes, halts the progression from premalignant to invasive pancreatic lesions in vivo. In the proposed study, we will examine the molecular mechanisms underlying the lack of proliferation observed in early stage PanINs and its relationship with oncogenic Ras signaling. We will take advantage of the conditional Sin3B allele we have generated in the mouse to assess the contribution of cell cycle exit and senescence as a tumor suppressor mechanism in the pancreas, using physiologically relevant cellular systems and mouse models. Specifically, we propose to: test the hypothesis that a Sin3B-dependent cell cycle withdrawal restricts Ras-induced pancreatic-tumor progression in vivo (Aim 1); and to identify the molecular pathways engaged by Ras activation in pancreatic ductal cells, in a Sin3B-dependent manner (Aim 2). To do so, we will use a physiologically relevant primary ductal cell culture system, and genetically engineered mouse models of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic ductal adenocarcinoma is virtually invariably a fatal disease, and is characterized by invasive and metastatic progression, as well as a striking resistance to conventional therapeutic approaches. Early pancreatic non-invasive lesions, known as pancreatic intraepithelial neoplasia (PanIN) are believed to represent initiating lesions in the generation of PDAC. Understanding the molecular events that allow the progression from PanINS to full cancer would provide new therapeutic opportunities in the treatment of pancreatic cancer.